ABSTRACT Traumatic spinal cord injuries (SCI) involve serious neural damage events that can lead to long-term motor and sensory deficits, as well as cognitive and emotional dysfunctions. Computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used in the clinical management of SCI. However, neither method provides physiological information of SCI progression and recovery. We propose to fill this gap by applying quantitative PET imaging using our newly developed synaptic vesicle glycoprotein 2A (SV2A) radiotracer to track the synaptic density changes and neuroplasticity over the disease course. Quantitative SV2A PET imaging has been used to reveal the synaptic density changes in a variety of neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, depression, epilepsy, schizophrenia, and stroke. Our pilot PET imaging studies using the recently developed SV2A PET imaging agents indicate that SV2A PET could be used to quantify synapse density in the spinal cord of rodents, monkeys, and human. Our pilot SV2A PET rodent imaging study proved the feasibility of using SV2A PET to detect subtle synaptic loss at 10 days post moderate thoracic contusion injury. Based on these preliminary results and literature evidence, we hypothesize that altered SV2A level is a biomarker for neuroplasticity in SCI and SV2A PET can be used to facilitate the diagnose and prognosis of SCI and to evaluate therapeutic effects in clinical trials. We propose to test the hypotheses through the following aims: 1) to determine the expression levels and dynamics of synaptic markers in rodent model of SCI over time, using molecular biology and quantitative in vitro imaging approach; 2) to validate SV2A PET imaging in the SCI rodent model through small animal PET, ex vivo and in vitro assays and behavioral tests and to apply SV2A PET imaging in the objective evaluation of therapeutic effects of an anti-Nogo antibody treatment; 3) as a key step for clinical translation and validation, we will select the most promising SV2A PET tracer for spinal cord imaging using nonhuman primate as the animal model. Successful completion of this project will yield a sensitive, reliable, and quantitative imaging method ready to be tested in SCI patients as a diagnosis and prognosis modality, as well as a research tool to probe the neuroplasticity in SCI animal models and patients. It will also allow for the objective and longitudinal tracking of SCI progression and recovery.